Research addressing the role of environmental chemicals in diabetes has rapidly expanded in the past several years and the 2011 Diabetes Strategic Plan from the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) acknowledges the need to understand more about the role of environmental exposures (NIDDK 2011). To help develop a research strategy, the NTP organized a state-of-the-science workshop in January 2011 to evaluate the current literature in terms of its evidence concerning associations between certain chemicals, including inorganic arsenic, and diabetes (National Toxicology Program 2011; Thayer et al. 2012). The experts who reviewed the literature on arsenic concluded that the epidemiological data provide limited to sufficient support for an association between arsenic and T2D in populations with relatively high exposure levels from drinking water such as Bangladesh and Taiwan. There was more uncertainty on associations in regions with lower exposure although recent studies using better measures of outcome and exposure support an association (Maull et al. 2012). This proposal addresses several research needs identified during the NTP workshop, in particular to: (1) expand environmental chemical research into investigations of T1D, and (2) evaluate the impact of early in life exposure in children and youth (Maull et al. 2012; Thayer et al. 2012). The potential future aims above would assess an additional research need of assessing the impact of environmental chemicals on the progression of the disease in diabetes (Maull et al. 2012; Thayer et al. 2012). The current literature refers to arsenic-induced diabetes as type 2 diabetes. No epidemiological studies have evaluated the association between arsenic and type 1 diabetes. Also, no experimental animal studies have been specifically designed to evaluate a potential role for arsenic in type 1 diabetes. However, several lines of evidence support consideration of arsenic in the etiology or pathogenesis of type 1 diabetes. First, there is some evidence that arsenic can affect the immune system (e.g., pro-inflammatory cytokines in plasma or immune response to influenza) , although autoimmune-related outcomes have been poorly studied for inorganic arsenic and its metabolites (Agency for Toxic Substances and Disease Registry (ATSDR) 2007). Second, the pancreas is recognized as a target tissue for various arsenic species in humans, animals, and in vitro models systems (Maull et al. 2012; Yorifuji et al. 2010). In addition, the phenotypic characterization of arsenic-associated diabetes is complex. A recent study involving 258 subjects from two arsenic-endemic regions of Mexico found that the prevalence of diabetes was positively associated with inorganic arsenic in drinking water (Del Razo et al. 2011). However, fasting plasma insulin and HOMA-IR were both inversely associated with arsenic concentrations in drinking water. In a large cross-sectional study in American-Indian adults, inorganic arsenic exposure was associated with diabetes prevalence. Among those without diabetes, arsenic was inversely related with the HOMA-IR, although the association was only borderline significant (p-value for trend 0.07) (Gribble et al. 2012). This pattern of higher fasting blood glucose (hyperglycemia) with lower fasting plasma insulin (hypoinsulinemia) suggests that arsenic-induced diabetes results in an impairment of &#946;-cell function, and is different from typical T2D, which is characterized by insulin resistance (i.e., increased HOMA-IR) in the presence of hyperinsulinemia. The negative associations between arsenic exposure and plasma insulin or HOMA-IR have also been reported in animal studies (Paul et al. 2011). Consistent with these results, tissue culture studies have demonstrated that exposure to submicromolar concentrations of inorganic arsenic or its methylated metabolites impairs insulin secretion by isolated pancreatic islets (personal communication with Mirek Styblo, provisionally accepted for publication in Toxicology and Applied Pharmacology) or beta-cells (Pi et al. 2010). In addition to the associations with diabetes, inorganic arsenic is a known human carcinogen and is associated with other adverse health effects in human including neurological, cardiovascular effects that include peripheral vascular disease (blackfoot disease), hypertension, ischemic heart disease (Agency for Toxic Substances and Disease Registry (ATSDR) 2007; Otto et al. 2007; Vahidnia et al. 2007), (Abhyankar et al. 2012; Medrano et al. 2010). With respect to the kidney, arsenic has been associated with kidney cancer and recent studies suggest impacts on renal function. Arsenic exposure in populations with high arsenic concentrations in drinking water (>50 g/L) in Bangladesh and China has been associated with increased proteinuria. In the US, at low-moderate levels of exposure, arsenic was associated with increased albuminuria, a marker of kidney damage, in American Indian adults who participated in the Strong Heart Study (Zheng et al. Am J Kidney Disease 2012 in press). In a small study in Taiwan, arsenic was also associated with reduced estimated glomerular filtration rate (Chen JW et al. Chemosphere 2011;84:17-24). Given those findings with diabetes-related complications and the fact that arsenic has been related to poor diabetes control in at least one study (Gribble et al. 2012), it is reasonable to hypothesize that arsenic exposure exacerbates complications of diabetes, even in the case that arsenic was not causally associated with diabetes.